Alzheimer's disease is the most common neurodegenerative disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated tau protein and by the formation of extracellular amyloid plaques. Abnormal deposition of tau into neurofibrillary tangles is also the primary pathologic feature of a group of less common disorders, collectively termed the tauopathies. To define the molecular mechanisms controlling tau-induced neurodegeneration we and others have modeled tauopathies in the simple and powerful genetic model organism Drosophila. Genetic, biochemical and cell biological experiments in Drosophila have provided important clues regarding the pathogenesis of tauopathies. However, the unbiased forward genetic screens providing the bases for these studies, while valuable, have to date remained incomplete. Here we propose to use newly created and powerful whole- genome transgenic RNAi collections to perform comprehensive genetic analysis of tau neurotoxicity in vivo. We will complement these studies by with a state of the art transcriptomics in human Alzheimer's disease neurons. These studies will for the first time provide a comprehensive analysis of mechanisms controlling tau toxicity to postmitotitc neurons and should identify many new high-value therapeutic targets. Our studies will be particularly important as more and more data emerges from genome wide associated studies showing genetic influences on Alzheimer's disease and related tauopathies, but with little clear evidence as to the mechanism of action of these newly identified gene products in neurodegenerative disease pathogenesis. PUBLIC HEALTH RELEVANCE: The proposed studies will combine the strengths of fruit flies as a fast, cheap model system to identify causal factors in tau neurotoxicity with state-of-the-art molecular analysis of tissue from patients with Alzheimer's disease to outline mechanisms controlling cell dysfunction and death in neurodegeneration. These studies will help us design better therapies for Alzheimer's disease and related neurodegenerative disorders.